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Biochemical analysis of recombinant CYP4A11 allelic variant enzymes: W126R, K276T and S353G
Han, S.,Cha, G.S.,Chun, Y.J.,Lee, C.H.,Kim, D.,Yun, C.H. JAPANESE SOCIETY FOR THE STUDY OF XENOBIOTICS 2016 DRUG METABOLISM AND PHARMACOKINETICS Vol.31 No.6
Human CYP4A11 is the major ω-hydroxylase of fatty acids in the liver and kidneys. It produces 20-hydroxyeicosatetraenoic acid as well as hydroxylates fatty acids. In this study, we investigated the biochemical properties of three alleles of CYP4A11: W126R, K276T, and S353G. Site-directed mutagenesis of the wild type CYP4A11 was performed, to construct the W126R, K276T, and S353G variant clones. The CYP4A11 wild type and variant constructs were heterologously expressed in Escherichia coli. CO-binding spectra showed the expression of the wild type, K276T and S353G variants, indicating the functional P450 holoenzyme. The W126R variant was not expressed in E. coli. Binding affinities of lauric acid in K276T and S353G variants were stronger than that of wild type. Steady-state kinetics in the hydroxylation reaction of fatty acids were studied. The catalytic efficiencies (k<SUB>cat</SUB>/K<SUB>m</SUB>) of K276T and S353G variants in the reactions without cytochrome b<SUB>5</SUB> were approximately 2- and 4-fold higher, respectively, than that of wild type, and in the reactions with cytochrome b<SUB>5</SUB> they were approximately 2- and 3-fold higher, respectively. These results suggest that individuals carrying the alleles, K276T and S353G, might exhibit higher catalysis of CYP4A11, which may affect the endogenous metabolic products associated with regulation of blood pressure.
Kim, Seong Soon,Im, So Hee,Yang, Jung Yoon,Lee, Yu-Ri,Kim, Geum Ran,Chae, Jin Sil,Shin, Dae-Seop,Song, Jin Sook,Ahn, Sunjoo,Lee, Hoi,Woo, Jae Chun,Ahn, Jin Hee,Yun, Chang Soo,Kim, Phiho,Kim, Hyoung Ra JAPANESE SOCIETY FOR THE STUDY OF XENOBIOTICS 2019 DRUG METABOLISM AND PHARMACOKINETICS Vol.34 No.1
Shrestha, Riya,Kim, Ju-Hyun,Nam, Wongshik,Lee, Hye Suk,Lee, Jae-Mok,Lee, Sangkyu Japanese Society for the Study of Xenobiotics 2018 DRUG METABOLISM AND PHARMACOKINETICS Vol.33 No.2
<P> Fisetin is a flavonol compound commonly found in edible vegetables and fruits. It has anti-tumor, antioxidant, and anti-inflammatory effects. Geraldol, the O-methyl metabolite of fisetin in mice, is reported to suppress endothelial cell migration and proliferation. Although the in vivo and in vitro effects of fisetin and its metabolites are frequently reported, studies on herbedrug interactions have not yet been performed. This study was designed to investigate the inhibitory effect of fisetin and geraldol on eight isoforms of human cytochrome P450 (CYP) by using cocktail assay and LC-MS/MS analysis. The selective inhibition of CYP2C8-catalyzed paclitaxel hydroxylation by fisetin and geraldol were confirmed in pooled human liver microsomes (HLMs). In addition, an IC<SUB>50</SUB> shift assay under different pre-incubation conditions confirmed that fisetin and geraldol shows a reversible concentration-dependent, but not mechanism-based, inhibition of CYP2C8. Moreover, Michaelis-Menten, Lineweaver-burk plots, Dixon and Eadie-Hofstee showed a non-competitive inhibition mode with an equilibrium dissociation constant of 4.1 μM for fisetin and 11.5 μM for geraldol, determined from secondary plot of the Lineweaver-Burk plot. In conclusion, our results indicate that fisetin showed selective reversible and non-competitive inhibition of CYP2C8 more than its main metabolite, geraldol, in HLMs. </P>
Modeling of aceclofenac metabolism to major metabolites in healthy volunteers
Kim, E.,Ihm, C.,Kang, W. JAPANESE SOCIETY FOR THE STUDY OF XENOBIOTICS 2016 DRUG METABOLISM AND PHARMACOKINETICS Vol.31 No.6
Aceclofenac has been used widely as a potent analgesic and anti-inflammatory drug. Aceclofenac is converted to 4'-hydroxyaceclofenac and diclofenac via CYP2C9-mediated hydroxylation and hydrolysis, respectively. CYP2C9 also mediates the hydroxylation of diclofenac to yield 4'-hydroxydiclofenac and the hydrolysis of 4'-hydroxyaceclofenac to 4'-hydroxydiclofenac. We aimed to model the metabolism of aceclofenac in volunteers using a compartmental modeling approach. After an oral dose of 100 mg aceclofenac in volunteers, plasma concentrations of aceclofenac and its three metabolites were measured. The pharmacokinetics of aceclofenac and the sequential formation of its three metabolites were analyzed using ADAPT 5. The delay parameter shifted the plasma aceclofenac concentration-time profile to the right and provided a large improvement of fit. Two compartments were needed to fit the aceclofenac and 4'-hydroxyaceclofenac data, and one additional compartment was sufficient to describe the time courses of the generated plasma concentrations of diclofenac and 4'-hydroxydiclofenac. The metabolism rate constant for 4'-hydroxyaceclofenac was much greater than that for diclofenac. The generation rate constant of 4'-hydroxydiclofenac from diclofenac was greater than that of its generation from 4'-hydroxyaceclofenac. Our model fully describes the time course of plasma aceclofenac concentration as well as the formation and disposition of its three major metabolites in volunteers.